The invention pertains to novel benzoxazole derivatives having drug and bio-affecting properties, to their preparation, to pharmaceutical formulations containing them and to methods of using them. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. In mammals, melatonin levels show a cyclical, circadian pattern, with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. 
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [125I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In the mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures.
Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [125I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting that melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487 published on Apr. 14, 1994.
Melatonin binding sites have been found in diverse tissues of the bodyxe2x80x94i.e., in the retina, superchiasmatic nucleus, spleen, etc. This means that melatonin exerts multiple physiological effects and is not highly selective. The potential for side effects with melatonin use is large. Melatonin agonists should be more selective than melatonin and have fewer side effects. Suitable melatonin agonists could overcome melatonin""s drawbacks, resulting in products having more predictable and, possibly, sustained activity.
Melatonin agonists should be particularly useful for the treatment of chronobiological disorders. They would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, periondontitis, immune disorders, neuroendocrine disorders, and a variety of sleep disorders.
Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as: 
wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application No. EP 527 687 A disclose, as melatonin ligands, ethylamines having cyclic substituents: 
wherein Arxe2x80x2 is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R1 is, inter alia, an alkyl or cycloalkyl group; and R2 is hydrogen or lower alkyl.
Matsuda, et al. in International Patent Application No. WO 95/22521 disclose 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as N-methyl-D-aspartate (NMDA) receptor antagonists, wherein R1 represents, inter alia, a C1-C5 linear saturated aliphatic, a C1-C5 linear unsaturated aliphatic, a branched aliphatic, or a phenyl group which may be substituted with one to three substituents selected independently from the group consisting of halogen, C1-C4 alkyl, nitro, amino, hydroxy, and C1-C4 alkoxy as shown below: 
The 1,2-diarylcyclopropane derivatives disclosed in NE 6701256 have CNS stimulant properties: 
wherein Ar1 and Ar2 are independently and optionally substituted phenyl; R1 is inter alia hydrogen, lower alkyl or acyl; R2 is inter alia alkyl, cycloalkyl or aralkyl.
Keavy et al. In U.S. Pat. No. 5,753,709 issued on May 19, 1998, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure: 
wherein X represents halogen, hydrogen, cyano, aryl, C1-4 alkyl or OR5 wherein, inter alia, R5 is hydrogen, C1-20 alkyl or C4-20 alkylcycloalkyl; Y is hydrogen or halogen; R is hydrogen, halogen or C1-4 alkyl; R1 is hydrogen, C1-4 alkyl or benzyl; and R2 is C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-4 alkoxyalkyl, C1-4 trifluoromethylalkyl or C2-8 alkylthioalkyl.
Catt et al. in U.S. Pat. No. 5,856,529 issued on Jan. 5, 1999, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure: 
wherein Q1 and Q2 represent hydrogen or halogen; X is CH2, CH or oxygen; Y is CR3, C3R4 or (CH2)n whereby n is 1 to 4; Z is CH2, CH or oxygen; R is hydrogen, halogen or C1-4 alkyl; m is 1 or 2; R2 is hydrogen or C1-4 alkyl; and R1 is C1-6 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C1-6 alkylamino, C2-6 alkenyl, C1-4 alkoxy(C1-4)alkyl, C1-4 alkylthio(C1-4)alkyl or C1-4 trifluoromethylalkyl.
Takaki et al. in U.S. Pat. No. 6,211,225 issued on Apr. 3, 2001, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure: 
wherein the wavy bondxcx9cxcx9crepresents the racemate, the (R)-enantiomer or the (S)-enantiomer; R1 and R2 each are independently hydrogen or halogen; W is CR5, CR5R6 or (CH2)n with n being 1 to 2; Z is CH2, CH or oxygen; R3 is hydrogen or C1-4 alkyl; R4 is C1-6 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C1-6 alkylamino, C2-6 alkenyl, C1-4 alkoxy(C1-4)alkyl, C1-4 alkylthio(C1-4)alkyl or C1-4 trifluoromethylalkyl; R5 and R6 are each independently hydrogen or C1-4 alkyl.
The foregoing disclosures do not teach or suggest the novel melatonergic benzoxazole derivatives of the present invention. The novel compounds of the present invention display melatonergic agonist activity.
The present invention is directed to, in a first aspect, a compound of Formula I: 
or a pharmaceutically acceptable salt or solvate thereof wherein
A is C1-4 alkylene or 1,2 disubstituted cyclopropyl;
B is C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, or C1-4 alkylamino;
X is hydrogen, halogen, C2-4 alkenyl, C1-6 alkyl, furyl, or phenyl optionally substituted with halogen, C1-6 alkoxy, or haloalkyl; and
Y is hydrogen, phenyl, or C1-6 alkyl optionally substituted with phenyl.
In another aspect, the present invention is directed to a method of treating a circadian rhythm-related disorder in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
In yet another aspect, the present invention is directed to a pharmaceutical composition for treating circadian rhythm-related disorders comprising a therapeutically effective amount of a compound as defined by Formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.
The present invention provides a novel series of compounds of Formula I and hydrates thereof: 
or a pharmaceutically acceptable salt or solvate thereof wherein
A is C1-4 alkylene or 1,2 disubstituted cyclopropyl;
B is C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, or C1-4 alkylamino;
X is hydrogen, halogen, C2-4 alkenyl, C1-6 alkyl, furyl, or phenyl optionally substituted with halogen, C1-6 alkoxy, or haloalkyl; and
Y is hydrogen, phenyl, or C1-6 alkyl optionally substituted with phenyl.
xe2x80x9cAlkenylxe2x80x9d means a straight or branched hydrocarbon radical containing a carbon-carbon double bond such as vinyl, propenyl, and butenyl.
xe2x80x9cAlkylxe2x80x9d means a straight or branched chain group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a divalent alkyl radical such as methylene, ethylene, propylene, butylene, and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to monovalent substituents of the structure: xe2x80x94O-alkyl, wherein alkyl is as defined above.
xe2x80x9cCycloalkylxe2x80x9d groups are cyclic alkyl moieties as used herein and in the claims to include such groups as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cyclopropyl group is a preferred cycloalkyl moiety.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine, or iodine. Preferred halogens in haloalkyl moieties are fluorine and chlorine.
xe2x80x9cHaloalkylxe2x80x9d includes straight and branched chain hydrocarbon radicals bearing from 1 to 3 halogen moieties.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein and in the claims is intended to include nontoxic inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric and the like, and nontoxic organic acids such as acetic, benzoic, fumaric, cinnamic, mandelic, succinic, citric, maleic, lactic and the like.
The term xe2x80x9chydrate or solvate thereofxe2x80x9d as used herein and in the claims is intended to include hydrated forms such as monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like as well as solvated forms. The products may be true hydrates, while in other cases, the products may merely retain adventitious water or be a mixture of water plus some adventitious solvent. It should be appreciated by those skilled in the art that hydrated and/or solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of Formula I encompass all pharmaceutically acceptable solvates, particularly hydrates, thereof. The present invention also encompasses diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of Formula I. Separation of individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods known to those of skill in the art.
Preferred compounds of the present invention may be further defined by the structure of Formula II: 
wherein
n is 2 to 4, preferably n is 3;
B is C1-3 alkyl, C3 cycloalkyl, C1-4 alkoxy, or C1-4 alkylamino;
X is hydrogen, halogen, C2-4 alkenyl, C1-2 alkyl, furyl, or phenyl optionally substituted with halogen, C1-2 alkoxy, or haloalkyl; and
Y is hydrogen, phenyl, or C1-4 alkyl group optionally substituted with phenyl.
The compounds of Formula II may be synthesized according to the following reaction schemes. 
Wherein Y is a methyl group, Reaction Scheme 1A illustrates a more precise route to the final product, particularly in Examples 1 to 6. 
In Reaction Scheme 1, the commercially available benzaldehyde 1 was homolygated with diethylcyanomethylphosphonate in a Horner-Emmons reaction. The resulting cinnamonitrile 2 was hydrogenated in the presence of the appropriate anhydride or acid chloride. Quenching this reaction mixture with aqueous sodium hydroxide selectively saponified the ester producing amides 3a to 3e. Heating these amides in the presence of pyridinium p-tolylsulfonate produced the benzoxazoles 4a to 4e. Hydrogenation of these nitrites with Raney nickel followed by acylation afforded examples 1 to 30 and 34 to 75.
In order to synthesize Examples 1 to 6, the commercially available benzaldehyde 1 was homolygated with diethylcyanomethylphosphonate in a Horner-Emmons reaction. The resulting cinnamonitrile 2 was hydrogenated with Raney Nickel which selectively saponified the ester in addition to reducing the nitrile. Heating the amine 4f in the presence of pyridinium p-tolylsulfonate produced the benzoxazole 5f which were later acylated to give the resultant benzoxazoles wherein Y is methyl.
Some preferred compounds prepared by Reaction Scheme 1 are
N-[3-(2-methylbenzoxazol-7-yl)propyl]propanamide;
N-[3-(2-methylbenzoxazol-7-yl)propyl]butanamide;
cyclopropyl-N-[3-(2-methylbenzoxazol-7-yl)propyl]carboxamide;
2-methyl-N-[3-(2-methylbenzoxazol-7-yl)propyl]propanamide;
N-[3-(2-ethylbenzoxazol-7-yl)propyl]propanamide;
N-[3-(2-ethylbenzoxazol-7-yl)propyl]butanamide;
cyclopropyl-N-[3-(2-ethylbenzoxazol-7-yl)propyl]carboxamide;
N-{3-[2-(4-phenylbutyl)benzoxazol-7-yl]propyl}acetamide;
N-{3-[2-(4-phenylbutyl)benzoxazol-7-yl]propyl}propanamide;
N-{3-[2-(4-phenylbutyl)benzoxazol-7-yl]propyl}butanamide;
2-methyl-N-{3-[2-(4-phenylbutyl)benzoxazol-7-yl]propyl}propanamide;
cyclopropyl-N-{3-[2-(4-phenylbutyl)benzoxazol-7-yl]propyl}carboxamide;
(ethylamino)-N-{3-[2-(4-phenylbutyl)benzoxazol-7-yl]propyl}carboxamide;
and N-(3-benzoxazol-7-ylpropyl)-2-methylpropanamide.
Some preferred compounds where there is X substitution on the benzoxazole ring include:
N-[3-(6-bromo-2-ethylbenzoxazol-7-yl)propyl]acetamide;
N-[3-(2-ethyl-6-vinylbenzoxazol-7-yl)propyl]acetamide;
cyclopropyl-N-[3-(2-ethyl-6-methylbenzoxazol-7-yl)propyl]carboxamide;
cyclopropyl-N-{3-[2-ethyl-6-(4-fluorophenyl)benzoxazol-7-yl]propyl}carboxamide;
N-{3-[2-ethyl-6-(4-methoxyphenyl)benzoxazol-7-yl]propyl}acetamide;
N-[3-(2-ethyl-6-phenylbenzoxazol-7-yl)propyl]acetamide;
cyclopropyl-N-[3-(2-ethyl-6-phenylbenzoxazol-7-yl)propyl]carboxamide;
N-[3-(2-ethyl-6-(2-furyl)benzoxazol-7-yl)propyl]acetamide; and
cyclopropyl-N-[3-(2-ethyl-6-(2-furyl)benzoxazol-7-yl)propyl]carboxamide.
When Y is hydrogen, the compounds may be synthesized in accordance with the following Reaction Scheme 2. 
Cinnamonitrile 2 was hydrogenated over 10% palladium on carbon in the presence of di-t-butyldicarbonate to give nitrile 6. Further hydrogenation with Raney nickel in the presence of the appropriate anhydride yielded compounds 7a to 7c. Deprotection of the BOC group with hydrochloric acid followed by cyclization with ethyl orthoformate produced examples 31 to 33.
Preferred compounds of the present invention include those of Formula I wherein A is a 1,2 disubstituted cyclopropyl as represented by Formula III: 
wherein
B is C1-6 alkyl group or C3 cycloalkyl group, or C1-4 alkylamino;
X is hydrogen, halogen, C2-4 alkenyl, C1-2 alkyl, furyl, or phenyl optionally substituted with halogen, C1-2 alkoxy, or haloalkyl; and
Y is hydrogen, phenyl, or C1-4 alkyl group optionally substituted with phenyl.
A more preferred group of compounds comprises X is hydrogen. The trans configuration of the compounds of Formula III is more preferred.
The compounds of Formula III may be synthesized in accordance with Reaction Scheme 3. 
Nitrosalicyaldehyde was homolygated by a Wittig reaction to give the cinnamate 9. Cyclopropanation to intermediate 10 was accomplished with diazomethane and palladium catalyzation. The nitro group was reduced and acetylated by hydrogenation in the presence of the appropriate anhydride or acid chloride to intermediates 11a to 11d. Cyclization to the benzoxazole 12a to 12d was accomplished by heating in the presence of pyridinium p-tolylsulfonate. The ester 12a to 12d was converted to the aldehyde 14a to 14d by reduction to the alcohol 13a to 13d followed by oxidation. Reduction of the oxime followed by acylation produced Examples 76 to 98.
Some preferred compounds of Formula III include:
N-{[(1R,2R)-2-(2-ethylbenzoxazol-7-yl)cyclopropyl]methyl}acetamide;
N-{[(1R,2R)-2-(2-ethylbenzoxazol-7-yl)cyclopropyl]methyl}propanamide;
N-{[(1R,2R)-2-(2-ethylbenzoxazol-7-yl)cyclopropyl]methyl}butanamide;
N-{[(1R,2R)-2-(2-ethylbenzoxazol-7-yl)cyclopropyl]methyl}-2-methylpropanamide;
N-{[(1R,2R)-2-(2-ethylbenzoxazol-7-yl)cyclopropyl]methyl}cyclopropylcarboxamide;
N-{[(1R,2R)-2-(2-ethylbenzoxazol-7-yl)cyclopropyl]methyl}(ethylamino)carboxamide;
N-{[(1R,2R)-2-(2-propylbenzoxazol-7-yl)cyclopropyl]methyl}acetamide;
N-({(1R,2R)-2-[2-(methylethyl)benzoxazol-7-yl]cyclopropyl}methyl)acetamide; N-{[(1R,2R)-2-(2-propylbenzoxazol-7-yl)cyclopropyl]methyl}propanamide;
N-({(1R,2R)-2-[2-(methylethyl)benzoxazol-7-yl]cyclopropyl}methyl)propanamide;
N-{[(1R,2R)-2-(2-propylbenzoxazol-7-yl)cyclopropyl]methyl}butanamide;
N-({(1R,2R)-2-[2-(methylethyl)benzoxazol-7-yl]cyclopropyl}methyl)butanamide;
N-{[(1R,2R)-2-(2-propylbenzoxazol-7-yl)cyclopropyl]methyl}-3-methylbutanamide;
N-({(1R,2R)-2-[2-(methylethyl)benzoxazol-7-yl]cyclopropyl}methyl)-3-methylbutanamide;
N-{[(1R,2R)-2-(2-propylbenzoxazol-7-yl)cyclopropyl]methyl}cyclopropylcarboxamide;
N-({(1R,2R)-2-[2-(methylethyl)benzoxazol-7-yl]cyclopropyl}methyl)cyclopropylcarboxamide;
N-{[(1R,2R)-2-(2-propylbenzoxazol-7-yl)cyclopropyl]methyl}(ethylamino)carboxamide;
N-({(1R,2R)-2-[2-(methylethyl)benzoxazol-7-yl]cyclopropyl}methyl)(ethylamino)carboxamide;
N-({(1R,2R)-2-[2-(4-phenylbutyl)benzoxazol-7-yl]cyclopropyl}methyl)acetamide;
N-({(1R,2R)-2-[2-(4-phenylbutyl)benzoxazol-7-yl]cyclopropyl}methyl)propanamide;
N-({(1R,2R)-2-[2-(4-phenylbutyl)benzoxazol-7-yl]cyclopropyl}methyl)butanamide;
N-({(1R,2R)-2-[2-(4-phenylbutyl)benzoxazol-7-yl]cyclopropyl}methyl)-2-methylpropanamide; and
N-({(1R,2R)-2-[2-(4-phenylbutyl)benzoxazol-7-yl]cyclopropyl}methyl)cyclopropylcarboxamide.
Biological Data:
The compounds of the present invention are melatonergic agents. They have been found to bind to human melatonergic receptors expressed in a stable cell line with good affinity. Further, the compounds are agonists as determined by their ability, like melatonin, to block the forskolin-stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the present invention should be useful as sedatives, chronobiotic agents, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents should find use in the treatment of stress, sleep disorders, seasonal depression, appetite regulation, shifts in circadian cycles, melancholia, benign prostate hyperplasia, inflammatory articular disease, periodontitis, and related conditions.
Melatonergic Receptor Binding Activity
1. Reagents:
(a) TME=50 mM Tris buffer containing 12.5 mM MgCl2, and 2 mM EDTA, pH 7.4 at 37xc2x0 C., with concentrated HCl.
(b) Wash buffer: 20 mM Tris base containing 2 mM MgCl2, pH 7.4 at room temperature.
(c) 10xe2x88x924 M melatonin (10xe2x88x925 M final concentration).
(d) 2-[125I]-iodomelatonin ML1a, 0.1 nM final concentration.
(e) 2-[125I]-iodomelatonin ML1b, 0.2 nM final concentration.
2. Membrane Homogenates: The melatonin ML1a and ML1b receptors cDNA were individually subcloned into pcDNA3 and introduced into NIH-3T3 cells using Lipofectamine. Transformed NIH-3T3 cells resistant to geneticin (G-418) were isolated, and single colonies expressing high levels of 2[125I]-iodomelatonin binding were isolated. Cells are maintained in DMEM supplemented with 10% calf serum and G-418 (0.5 g/liter). Cells are grown to confluency in T-175 flasks, scraped using Hank""s balanced salt solution, and frozen at xe2x88x9280xc2x0 C. For preparing membrane homogenates, pellets are thawed on ice, and re-suspended in TME buffer in the presence of 10 xcexcg/ml aprotinin and leupeptin, and 100 xcexcM phenylmethylsulfonylfluoride. The cells were then homogenized using a dounce homogenizer, and centrifuged. The resulting pellet was re-suspended with dounce homogenizer in TME (supplemented with the above protease inhibitors) and frozen. On the day of assay, a small aliquot was thawed on ice and re-suspended in the ice cold TME (1:50-1:100 v/v) and held on ice until assayed.
3. Incubation: 37xc2x0 C. for 1 hour. Reaction is terminated by filtration. Filters were washed 3 times.
4. References: Reppert, S. M. et al., Neuron, 13, p. 1177-1185 (1994); and Reppert, S. M. et al., Proc. Natl. Acad. Sci. USA, 92, p. 8734-8738 (1995).
Based on biological tests, the following Formula I compounds are preferred. Those with binding affinities for the human melatonin receptor with IC50 of 250 nM or less are most preferred. All Formula I compounds are shown in Tables I to III.
The compounds of the present invention have affinity for receptors of the endogenous pineal hormone, melatonin, as determined in receptor binding assays described above in Tables I to III for the ML1a and ML1b (human) receptors. Melatonin is involved in the regulation of a variety of biological rhythms and exerts its biological effects via interaction with specific receptors. There is evidence that administration of melatonin agonists are of clinical utility in the treatment of various conditions regulated by melatonin activity. Such conditions include depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, some disorders associated with reproduction, cancer benign prostatic hyperplasia, immune disorders, and neuroendocrine disorders.
For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally with pharmaceutically acceptable adjuvants and excipients employing standard conventional techniques.
The pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) transdermal, bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and the like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I in oral dosage formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See for example, Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.
In making pharmaceutical compositions containing compounds of the present invention, the active ingredient(s) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient, and mode of administration, but also on the degree of melatonergic activity desired and the potency of the particular compound being utilized for the particular disorder or condition concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to 100 mg, more usually 1 to 10 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
These active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.1 to 500 mg. In the treatment of adult humans, the range of about 0.1 to 10 mg/day, in single or divided doses, is preferred. Generally, the compounds of the invention may be used in treating sleep and related disorders in a manner similar to that used in treating sleep and related disorders in a manner similar to that used for melatonin.
However, it will be understood that the amount of the compound actually administered will be determined by a physician, in light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight and response of the individual patient, and the severity of the patient""s symptoms.
The compounds which constitute this invention, their methods of preparation and their biologic actions will appear more fully from consideration of the following examples, which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope.
Intermediates 2 to 15d illustrated in Reaction Schemes 1 to 3 above were made in accordance with the experimentals below. The intermediates were then used to synthesize Examples 1 to 98.
In the following intermediates and examples, used to illustrate the foregoing synthetic processes, all temperatures are expressed in degrees Celsius and melting points are uncorrected. Proton magnetic resonance (1H NMR) and carbon magnetic resonance (13C NMR) spectra were determined in the solvents indicated and chemical shifts are reported in xcex4 units downfield from the internal standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublet; bd, broad doublet; dt, doublet of triplet; bs, broad singlet; dq, doublet quartet. The infrared (IR) spectral descriptions include only absorption wave numbers (cmxe2x88x921) having functional group identification value. The IR determinations were employed using the compound neat as a film or by employing potassium bromide (KBr) as diluent. Optical rotations [xcex1]D25 were determined in the solvents and concentration indicated. Low resolution mass spectra (MS) are reported as the apparent molecular weight (M+H)+. The elemental analyses are reported as percent by weight.
Diethyl cyanomethyl phosphonate (21.24 g) was added dropwise to a suspension of NaH (7.2 g, 60%) in THF (200 mL) at 0xc2x0 C. After stirring for 1 h, a solution of 3-nitrosalicylaldehyde 1 (10 g) in THF (40 mL) was added. The resulting mixture was stirred for 1 h and quenched with water. After the THF was removed, the residue was extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated to give a residue. The residue was purified by flash chromatography over silica gel (elution with dichloromethane) to give 11 g (95%) of the desired compound 2.
IR (film, cmxe2x88x921) 3228 (br), 2221; 1H NMR (300 MHz, CDCl3): xcex48.20 (dd, J=8.4, 1.6 Hz, 1H), 7.73-7.70 (m, 1H), 7.64 (d, J=16.8 Hz, 1H), 7.08 (t, =7.7 Hz, 1H), 6.26 (d, J=16.8 Hz, 1H); 13C NMR (75 MHz,CDCl3) xcex4153.8, 143.7, 136.4, 134.3, 127.3, 125.0, 120.1, 118.0, 100.6; MS(ESI) 189 (Mxe2x88x92H)+.
A suspension of 2 (5.044 g), 10% Pd/C (1 g), and (EtCO)2O (5.004 g) was hydrogenated at 50 psi for 16 h. After filtration, the filtrate was quenched with 10N NaOH. After the THF was removed, the residue was acidified and extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated to give a residue. The residue was purified by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) to give 5.5 g (97%) of the desired compound 3a.
IR (film, cmxe2x88x921) 3283 (br), 1637; 1H NMR (300 MHz, CDCl3): xcex49.41 (s, 1H), 7.87 (br s, 1H), 7.03-6.93 (m, 1H), 6.75-6.69 (m, 2H), 2.97 (t, J=7.0 Hz, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.44 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4175.0, 147.5, 129.0, 128.2, 125.9, 121.9, 120.2, 120.0, 29.8, 27.5, 17.4, 9.9; MS(ESI) 217 (Mxe2x88x92H)+.
The compound was prepared by the general procedure described in 3a using 2 (1940 mg), 10% Pd/C (400 mg), and (n-PrCO)2O (2 g). Purification by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) gave 1856 mg (80%) of the desired product.
IR (film, cmxe2x88x921) 3307(br), 1644; 1H NMR (300 MHz, CDCl3): xcex47.07-7.05 (m, 1H), 6.82-6.75 (m, 2H), 3.03 (t, J=7.1 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.49 (t, J=8.9 Hz, 2H), 1.82-1.70 (m, 2H), 1.04 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4174.3, 147.7, 129.2, 128.3, 126.0, 121.9, 120.3, 120.1, 38.7, 27.6, 19.4, 17.5, 13.7; MS(ESI) 231 (Mxe2x88x92H)+; Anal Calcd for C13H16N2O2 C, 67.22; H, 6.94. Found: C, 67.25; H, 6.92.
The compound was prepared by the general procedure described in 3a using 2 (2.53 g), 10% Pd/C (0.5 g), and isobutyric anhydride (4.21 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 2.18 g (71%) of the desired product.
1H NMR (300 MHz, CDCl3) xcex47.44 (br, s, 1H), 7.10 (dd, J=6.6, 2.4 Hz, 1H), 6.86-6.78 (m, 2H), 3.02 (t, J=7.2 Hz, 2H), 2.75-2.62 (m, 3H), 1.31 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) xcex4177.9, 147.6, 129.4, 128.3, 125.7, 121.6, 120.1, 120.0, 36.1, 27.6, 19.7, 17.3; MS (ESI): 233 (M+H)+.
A suspension of 2 (5.7 g), 10% Pd/C (1 g), and (EtCO)2O (5.004 g) was hydrogenated at 50 psi for 16 h to yield (t-butoxy)-N-[3-(2-cyanoethyl)-2-hydroxyphenyl]carboxamide, Intermediate 6 below. Purification by flash chromatography over silica gel eluting with EtOAc gave 7.4 g (94%) of product. A mixture of 15 (7.205 g) and 60 mL of 4 N HCl in EtOAc (100 mL) at 40xc2x0 C. was stirred for 2 h. After cooling to rt, the mixture was diluted with ether and based to neutral. The organic layer was washed with brine, dried with MgSO4, concentrated to give 2.0 g (45%) of a crude product that was used in the next step without purification. A solution of 5-phenyl valeryl chloride (576 mg) in methylene chloride (1 mL) was added a solution of the above product (486 mg) and Et3N (606 mg) in methylene chloride (6 mL). After stirring for 1 h, purification by flash chromatography over silica gel (elution with 50% EtOAc/hexanes) gave 786 mg (81%) of the desired product.
IR (film, cmxe2x88x921) 3307(br), 1644; 1H NMR (300 MHz, CDCl3): xcex47.61 (s, 1H), 7.54-7.06 (m, 6H), 6.91-6.72 (m, 2H), 3.03 (t, J=7.3 Hz, 2H), 2.80-2.65 (m, 4H), 2.48 (t, J=5.5 Hz, 2H), 1.29-1.24 (m, 4H); 13C NMR (75 MHz,CDCl3) xcex4174.0, 147.7, 142.0, 129.3, 128.6, 128.5, 126.1, 126.0, 125.8, 121.8, 120.3, 120.0, 36.8, 35.7, 30.9, 27.7, 25.5, 17.5; MS(ESI) 321 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described in 3a using 2 (1940 mg), 10% Pd/C (400 mg), and (PhCO)2O (4.2 g). Purification by flash chromatography over silica gel (elution with 50% EtOAc/hexanes) gave 2632 mg (99%) of the desired product.
IR (film, cmxe2x88x921) 3315(br), 1637; 1H NMR (300 MHz, CDCl3): xcex48.22 (br s, 1H), 7.89 (dd, J=7.0, 1.4 Hz, 1H), 7.62-7.47 (m, 3H), 7.11 (d, J=7.2 Hz, 1H), 6.95 (dd, J=8.0, 1.6 Hz, 1H), 6.86 (t, J=7.9 Hz, 1H), 3.04 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H); 13C NMR (75 MHz,CDCl3) xcex4167.7, 147.8, 132.8, 132.7, 129.4, 129.1, 128.6, 127.5, 125.8, 122.3, 120.4, 119.9, 27.6, 17.5; MS(ESI) 265 (Mxe2x88x92H)+.
A solution of 2 (3.49 g, 18.4 mmol) in Ac2O (150 mL) containing 10% Pd/C (2.0 g) was hydrogenated in a Parr apparatus at 50 psi for 2 h. The catalyst was then removed by filtration over Celite, and the filtrate was poured gradually into 2 N NaOH (1.0 L), and stirred until the anhydride was completely hydrolyzed, as evidenced by the formation of a single phase. The solution was cooled to room temperature, and was extracted with CH2Cl2. The organic extract was dried (Na2SO4), and was then subjected to chromatography (SiO2:CH2Cl2/MeOH/30% aq NH3 95/4.5/0.5). After solvent removal, the residue was triturated in CH2Cl2:Et2O 1:1, collecting a white solid in two crops to afford 2.58 g (57% yield): MS (ESI) m/z 245.22 (MHxe2x88x92); IR (KBr) 2247 cmxe2x88x921; 1H NMR (CDCl3) xcex47.95 (d, 1H, J=8.1 Hz), 7.25 (t, 1H, J=7.8 Hz), 7.08 (m, 2H), 2.86 (t, 2H, J=7.5 Hz), 2.59 (t, 2H, J=7.5 Hz), 2.42 (s, 3H), 2.18 (s, 3H); 13C NMR (CDCl3) xcex4168.9, 168.5, 140.2, 131.0, 130.7, 127.3, 126.0, 123.6, 119.0, 26.7, 24.6, 20.9, 17.9; Anal. Calcd for C13H14N2O3.0.2 H2O: C, 62.49; H, 5.81; N, 11.21. Found: C, 62.59; H, 5.83; N, 10.81.
A solution of 3a (1.5 g) and PPTS (500 mg) in xylene (40 mL) was refluxed for 2 h. After cooling to rt, the reaction was quenched with water and diluted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% EtOAc/hexanes) to give 1.33 g (95%) of the desired compound.
IR (film, cmxe2x88x921) 3224, 1612; 1H NMR (300 MHz, CDCl3): xcex47.58 (dd, J=7.8, 1.1 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.15 (dd, J=7.5, 0.5 Hz, 1H), 3.23 (t, J=7.4 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.71 (t,=7.5 Hz, 2H), 1.46 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4168.1, 149.2, 141.6, 124.6, 124.5, 120.9, 118.9, 118.8, 32.1, 23.6, 17.8, 11.0; MS(ESI) 200 (M)+.
The title compound was prepared by the general procedure described in 4a using 3b (1500 mg) PPTS (487 mg). Purification by flash chromatography over silica gel (elution with 50% EtOAc/hexanes) gave 1313 mg (95%) of the desired product.
IR (film, cmxe2x88x921) 3455; 1H NMR (300 MHz, CDCl3): xcex47.61 (dd, J=7.8, 1.1 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 3.26 (t, J=7.5 Hz, 2H), 2.95 (q, J=7.4 Hz, 2H), 2.78 (t,=7.5 Hz, 2H), 2.04-1.87 (m, 2H), 1.09 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4167.3, 149.3, 141.5, 124.8, 124.7, 121.0, 119.0, 118.9, 30.6, 26.4, 20.4, 17.9, 13.9;
MS(ESI) 213 (Mxe2x88x921)+; Anal Calcd for C13H14N2O C, 72.87; H, 6.59. Found: C, 72.70; H, 6.60.
The title compound was prepared by the general procedure described in 4a using 3c (2.08 g), PPTS (0.68 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 1.84 g (96%) of desired product.
1H NMR (300 MHz, CDCl3) xcex47.59 (d, J=7.2 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H). 7.15 (d, J=7.4 Hz, 1H), 3.29-3.18 (m, 3H), 2.77 (t, J=7.4 Hz, 2H), 1.46 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) xcex4171.2, 149.0, 141.3, 124.5, 124.4, 120.8, 118.7, 118.6, 28.8, 26.2, 20.2, 17.6; MS (ESI): 215 (M+H)+.
The title compound was prepared by the general procedure described in 4a using 3d (750 mg) and PPTS (175 mg). Purification by flash chromatography over silica gel (elution with 50% EtOAc/hexanes) gave 670 mg (95%) of the desired product.
IR (film, cmxe2x88x921) 2247; 1H NMR (300 MHz, CDCl3): xcex47.62 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 7H), 3.26 (t, J=7.5 Hz, 2H), 3.02 (t, J=7.3 Hz, 2H), 2.94-2.78 (m, 4H), 1.96-1.74 (m, 4H); 13C NMR (75 MHz, CDCl3) xcex4167.2, 149.2, 142.0, 141.3, 128.6, 128.5, 126.0, 124.9, 124.8, 121.1, 119.0, 118.8, 35.6, 31.0, 28.6, 26.5, 26.4; MS(ESI) 303 (Mxe2x88x92H)+.
Anal Calcd for C20H20N2O C, 78.92; H, 6.62; Found: C, 78.78; H, 6.60.
The title compound was prepared by the general procedure described in 4a using 3e (19950 mg) and PPTS (565 mg). Purification by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) gave 1786 mg (96%) of the desired product.
IR (film, cmxe2x88x921) 2247; 1H NMR (300 MHz, CDCl3): xcex48.27-8.21 (m, 2H), 7.70 (dd, J=7.9, 1.1 Hz, 1H), 7.56-7.34 (m, 3H), 7.31 (t, J=7.2 Hz, 1H), 7.22 (t, J=6.6 Hz, 1H), 3.34 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H); 13C NMR (75 MHz,CDCl3) xcex4163.0, 149.1, 142.3, 131.8, 129.0, 127.7, 126.9, 125.3, 125.1, 121.2, 119.3, 118.9, 26.4, 17.8; MS(ESI) 247 (Mxe2x88x92H)+.
A solution of 3f (2.58 g, 10.5 mmol) in 200 mL of MeOH:30% aq NH3 (85:15) containing Raney nickel was hydrogenated in a Parr apparatus at 50 psi for 1 h. The catalyst was removed by filtration over Celite, and the solvent was removed in vacuo. The residue was taken up in CH2Cl2 and the resulting solution was dried (Na2SO4), followed by the addition of ether. A light gray solid was isolated by filtration to furnish 1.7 g (78% yield).
MS (ESI) m/z 209.17 (MH+); 1H NMR (DMSO-d6) xcex49.03 (br s, 1H), 7.73 (d, 1H, J=7.5 Hz), 6.72 (d, 1H, J=7.2 Hz), 6.52 (t, 1H, J=7.5 Hz), 6.16 (br s, 3H), 2.63 (m, 2H), 2.49 (m, 2H), 2.06 (s, 3H), 1.72 (m, 2H); 13C NMR (DMSO-d6) xcex4168.1, 149.1, 127.7, 127.6, 127.4, 124.9, 118.0, 116.5, 37.5, 26.5, 24.1, 14.0; Anal. Calcd for C11H16N2O2.0.2 H2O: C, 62.36; H, 7.80; N, 13.22; Found: C, 62.33; H, 7.75; N, 13.11.
A suspension of 4a (1.25 g) and Raney Nickel (1 mL) in MeOH/NH3.H2O(50/15 mL) was hydrogenated at 50 psi for 1.5 h. After filtration, the MeOH was removed. The residue was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give 1.25 g (99%) of the desired product which was used in the next step without purification.
1H NMR (300 MHz, CDCl3): xcex47.52 (dd, J=7.8, 0.5 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.11 (d, J=7.4 Hz, 1H), 3.00-2.82(m, 6H), 2.04-1.86 (m, 2H), 1.48 (t,=7.5 Hz, 3H).
The title compound was prepared by the general procedure described in 5a using 4b (1284 mg). Work-up gave 1.30 g (100%) of the desired product which was used in the next step without purification.
The title compound was prepared by the general procedure described in 5a using 4c (1.78 g), Raney Nickel (1 ml) in MeOH/NH3.H2O (70/20 ml) to give 1.81 g (100%) of crude product.
MS (ESI): 219 (M+H)+.
The title compound was prepared by the general procedure described in 5a using 4d (670 mg). Work-up gave 640 mg (95%) of the desired product which was used in the next step without purification.
The title compound was prepared by the general procedure described in 5a using 4e (1480 mg). Work-up gave 1500 mg (100%) of the desired product which was used in the next step without purification.
A solution of 4f (1.5 g, 7.2 mmol) and pyridinium p-toluenesulfonate (450 mg, 1.8 mmol) in xylene (250 mL) was refluxed overnight, using a Dean-Stark trap. The resulting solution was poured hot over a silica gel bed, eluting with CH2Cl2:MeOH:30% aq NH3 (96:3.6:0.4). After solvent removal, the residue was taken up in a minimum of CH2Cl2, to which 1N HCl/Et2O (5 mL) was added, resulting in the formation of a precipitate. The precipitate was collected by filtration to afford a white solid (0.69 g, 43% yield).
MS (ESI) m/z 191.20 (MH+); 1H NMR (DMSO-d6) xcex48.13 (br s, 3H), 7.49 (d, 1H, J=7.5 Hz), 7.22 (m, 2H), 2.90 (m, 2H), 2.76 (m, 2H), 2.60 (s, 3H), 2.00 (m, 2H); 13C NMR (DMSO-d6) xcex4163.6, 149.0, 124.5, 124.3, 123.7, 117.0, 38.4, 27.0, 26.3, 14.2; Anal. Calcd for C11H14N2O.HCl.0.5 H2O: C, 56.05; H, 6.41; N, 11.88; Found: C, 55.74; H, 6.52; N, 11.79.
A suspension of 2 (5.7 g), 10% Pd/C (1 g), and (EtCO)2O (5.004 g) was hydrogenated at 50 psi for 16 h to yield (t-butoxy)-N-[3-(2-cyanoethyl)-2-hydroxyphenyl]carboxamide. Purification by flash chromatography over silica gel eluting with EtOAc gave 7.4 g (94%) of product. IR (film, cmxe2x88x921) 3312, 1678; 1H NMR (300 MHz, CDCl3): xcex47.04(dd, J=7.5, 0.8 Hz, 1H), 6.88-6.75 (m, 2H), 3.03(t, J=7.3 Hz, 2H), 2.73(t, J=7.3 Hz, 2H), 1.54(s, 9H); 13C NMR (75 MHz,CDCl3) xcex4155.9, 146.9, 129.0, 127.5, 125.5, 121.6, 120.6, 119.9, 83.0, 28.6, 27.6, 17.6; MS(ESI) 261 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described above using 6 (1.04 g), Raney-nickel (2 mL), and (MeCO)2O (2 mL). Purification by flash chromatography over silica gel (elution with EtOAc) gave 400 mg (32%) of the desired compound.
IR (film, cmxe2x88x921) 3312, 1678; 1H NMR (300 MHz, CDCl3): xcex47.04(d, J=7.7 Hz, 1H), 6.88-6.75 (m, 2H), 3.24(q, J=6.1 Hz, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.05 (s, 3H), 1.85-1.77 (m, 2H), 1.52 (s, 9H); 13C NMR (75 MHz,CDCl3) xcex4171.2, 155.0, 145.5, 130.6, 126.7, 126.1, 120.7, 119.0, 81.7, 38.8, 31.0, 28.4, 27.2, 23.5; MS(ESI) 307 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described above using 6 (1.04 g), Raney-nickel (2 mL), and (EtCO)2O (2 mL). Purification by flash chromatography over silica gel (elution with EtOAc) gave 350 mg (27%) of the desired compound.
IR (film, cmxe2x88x921) 3302, 1678; 1H NMR (300 MHz, CDCl3): xcex47.04(dd, J=7.7, 0.8 Hz, 1H), 6.88-6.78 (m, 2H), 3.24 (q, J=6.1 Hz, 2H), 2.73 (t, J=6.6 Hz, 2H), 2.27 (q, J=7.5 Hz, 2H), 1.85-1.77 (m, 2H), 1.52 (s, 9H), 1.19 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4175.0, 154.9, 145.4, 130.5, 126.8, 126.0, 120.7, 118.8, 81.6, 38.6, 31.5, 30.0, 28.4, 27.2, 10.0; MS(ESI) 321 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described above using 6 (1.04 g), Raney-nickel (2 mL), and (i-PrCO)2O (2 mL). Purification by flash chromatography over silica gel (elution with EtOAc) gave 375 mg (28%) of the desired compound.
IR (film, cmxe2x88x921) 3305, 1670; 1H NMR (300 MHz, CDCl3): xcex47.04(dd, J=7.6, 1.8 Hz, 1H), 6.88-6.78 (m, 2H), 3.24 (q, J=6.1 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.42-2.33 (m, 1H), 1.87-1.73 (m, 2H), 1.52 (s, 9H), 1.26 dt, J=8.0 Hz, 6H); 13C NMR (75 MHz,CDCl3) xcex4178.2, 154.8, 145.3, 130.4, 126.9, 125.9, 120.7, 118.6, 81.5, 38.4, 36.0, 31.8, 28.4, 27.1, 19.8; MS(ESI) 335 (Mxe2x88x92H)+.
A mixture of 7a (308 mg) and 2 mL of 6N HCl in EtOAC (10 mL) was stirred at 40xc2x0 C. for 1 h. After cooling, the reaction mixture was neutralized with 1 N NaOH. Work-up gave 139 mg (67%) of the desired product that was used in the next step without purification.
1H NMR (300 MHz, CDCl3): xcex46.73-6.52 (m, 3H), 3.22 (m, 2H), 2.65 (t, J=7.0 Hz, 2H), 1.94 (s, 3H) 1.82-1.73 (m, 2H).
A mixture of 7b (322 mg) and 2 mL of 6N HCl in EtOAC (10 mL) was stirred at 40xc2x0 C. for 1 h. After cooling, the reaction mixture was neutralized with 1 N NaOH. Work-up gave 144 mg (65%) of the desired product that was used in the next step without purification or analysis.
A mixture of 7c (336 mg) and 2 mL of 6N HCl in EtOAC (10 mL) was stirred at 40xc2x0 C. for 1 h. After cooling, the reaction mixture was neutralized with 1 N NaOH. Work-up gave 170 mg (72%) of the desired product that was used in the next step without purification.
1H NMR (300 MHz, CDCl3): xcex46.73-6.46 (m, 3H), 3.28(m, 2H), 2.67 (t, J=6.5 Hz, 2H), 2.44-2.31 (m, 1H) 1.82-1.73 (m, 2H), 1.21 (d, J=6.0 Hz, 6H).
A solution of 3-nitrosalicylaldehyde (20 g) and Ph3PCHCO2Et (63 g) in THF (300 mL) was refluxed for 2 h. After concentration, the residue was purified by flash chromatography over silica gel (elution with CH2Cl2) to give 25.6 g (90%) of the desired compound. No analysis was undertaken.
Methyl-3-nitro-1-nitrosoquanidine (73 g) was carefully added to a mixture of 10 N NaOH (200 mL) and ether (640 mL) at 0xc2x0 C. portionwise. After stirring for 0.5 h, the ether layer was decanted into a solution of 9 (10.65 g) and Pd(OAc)2 (1 g) at 0xc2x0 C. After stirring for 0.5 h and filtering, the filtrate was concentrated and purified by flash chromatography over silica gel (elution with 10% EtOAc/hexanes) to give 8 g (70%) of the desired compound.
IR (film, cmxe2x88x921) 3218, 1724; 1H NMR (300 MHz, CDCl3): xcex47.99 (d, J=8.5 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.97 (t, J=8.4 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 2.80-2.73 (m, 1H), 1.90-1.84 (m, 1H), 1.71-1.60 (m, 1H), 1.38-1.31 (m, 1H), 1.08 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4173.2, 154.5, 134.2, 133.7, 131.4, 123.4, 119.5, 61.0, 22.8, 20.7, 15.3, 14.4; MS(ESI) 250 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described in 3a using 10 (2.27 g), 10% Pd/C (400 mg), and (EtCO)2O (5.004 g). Purification by flash chromatography over silica gel (elution with 10% EtOAc/hexanes) gave 2.37 g (94%) of the desired compound.
IR (film, cmxe2x88x921) 3212, 1704; 1H NMR (300 MHz, CDCl3): xcex46.93-6.87 (m, 1H), 6.76-6.70 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 2.80-2.73 (m, 1H), 2.49 (q, J=7.5 Hz, 2H), 1.88-1.82 (m, 1H), 1.54-1.46 (m, 1H), 1.31-1.01 (m, 7H); 13C NMR (75 MHz,CDCl3) xcex4174.5, 174.0, 148.0, 130.3, 125.8, 123.8, 120.7, 120.0, 60.8, 30.1, 22.8, 21.6, 15.7, 14.3, 14.2, 9.9; MS(ESI) 276 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described in 11a using 10 (2.51 g), 10% Pd/C (0.5 g), and n-butyric anhydride (1.74 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 2.45 g (84%) of desired product.
1H NMR (300 MHz, CDCl3) xcex48.92 (br, s, 1H), 8.25 (br, s, 1H), 6.90 (dd, J=5.6, 3.9 Hz, 1H), 6.75-6.70 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 2.84-2.75 (m, 1H), 2.40 (t, J=7.4 Hz, 2H), 1.91-1.83 (m, 1H), 1.78-1.67 (m, 2H), 1.58-1.51 (m, 1H), 1.35-1.23 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) xcex4173.9, 173.8, 148.0, 130.1, 125.8, 123.7, 120.7, 119.8, 60.6, 38.6, 22.7, 21.5, 19.2, 15.6, 14.2, 13.5; MS (ESI): 292 (M+H)+.
The title compound was prepared by the general procedure described in 11a using 10 (2.51 g), 10% Pd/C (0.5 g), and isobutyric anhydride (1.74 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 2.31 g (79%) of desired product.
1H NMR (300 MHz, CDCl3) xcex48.82 (br, s, 1H), 8.25 (br, s, 1H), 6.93 (dd, J=6.2, 3.3 Hz, 1H), 6.78-6.75 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.83-2.76 (m, 1H), 2.72-2.59 (m, 1H), 1.90-1.83 (m, 1H), 1.61-1.53 (m, 1H), 1.38-1.23 (m, 10H); 13C NMR (75 MHz, CDCl3) xcex4177.5, 173.8, 148.0, 130.2, 125.7, 123.8, 120.5, 119.9, 60.6, 36.0, 22.6, 21.5, 19.6, 15.5, 14.2; MS (ESI): 292 (M+H)+.
A suspension of Raney-nickel (1 mL) and 10 (1135 mg) in THF was hydrogenated at 50 psi for 2 h. After filtration, the filtrate was concentrated to give 985 mg (100%) of a crude product that was used in the next step without purification. The title compound was prepared by the general procedure described above using the above crude product 985 mg), Ph(CH2)4COCl (960 mg), and Et3N (101 mg). Purification by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) gave 1749 mg (98%) of the desired compound.
IR (film, cmxe2x88x921) 3308, 1724; 1H NMR (300 MHz, CDCl3): xcex47.32-7.17 (m, 5H), 6.90-6.74 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.80-2.76 (m, 1H), 2.69(t, J=7.3 Hz, 2H), 2.48 (t, J=7.0 Hz, 2H), 2.05-1.56 (m, 6H), 1.33-1.07 (m, 4H); 13C NMR (75 MHz,CDCl3) xcex4173.9, 173.5, 148.1, 142.0, 130.5, 128.6, 126.1, 125.8, 124.1, 120.6, 120.1, 60.8, 37.0, 35.7, 31.0, 25.5, 22.8, 21.6, 15.8, 14.4; MS(ESI) 380 (Mxe2x88x92H)+.
The title compound was prepared by the general procedure described in 4a using 11a (2.043 g) and PPTS (678 mg). Purification by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) gave 1626 mg (90%) of the desired product.
1H NMR (300 MHz, CDCl3): xcex47.52 (dd, J=7.9, 1.0 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.00 (q, J=7.5 Hz, 2H), 2.80-2.73 (m, 1H), 2.21-2.15 (m, 1H), 1.67-1.60 (m, 1H), 1.58-1.41 (m, 1H), 1.47 (t, J=7.5 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4173.3, 168.2, 149.2, 141.1, 124.3, 123.8, 121.9, 117.5, 60.9, 22.9, 22.2, 21.6, 16.2, 14.3, 11.0; MS(ESI) 260 (M+H)+.
The title compound was prepared by the general procedure described in 12a using 11b (2.37 g), PPTS (0.60 g). Purification by flash chromatography over silica gel, elution with 30% ETOAc/hexanes, gave 1.93 g (87%) of desired product.
1H NMR (300 MHz, CDCl3) xcex47.50 (d, J=7.9 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H). 6.96 (d, J=7.6 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.82-2.74 (m, 1H), 2.22-2.16 (m, 1H), 1.98-1.26 (m, 2H), 1.71-1.64 (m, 1H), 1.61-1.54 (m, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.05 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) xcex4173.3, 167.0, 149.1, 141.4, 124.0, 123.6, 124.7, 117.4, 60.7, 30.4, 22.7, 21.5, 20.2, 16.0, 14.2, 13.6; MS (ESI): 274 (M+H)+.
The title compound was prepared by the general procedure described in 12a using 11c (2.21 g), PPTS (0.57 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 1.97 g (95%) of desired product.
1H NMR (300 MHz, CDCl3) xcex47.52 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H). 6.97 (d, J=7.6 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.32-3.17 (m, 1H), 2.82-2.74 (m, 1H), 2.23-2.17 (m, 1H), 1.72-1.66 (m, 1H), 1.62-1.56 (m, 1H), 1.47 (d, J=7.0 Hz, 6H), 1.30 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) xcex4173.2, 171.1, 149.1, 141.3, 124.0, 123.7, 121.7, 117.5, 60.7, 29.8, 22.7, 21.6, 20.2, 16.1, 14.2; MS (ESI): 274 (M+H)+.
The title compound was prepared by the general procedure described in 12a using 11d (1.61 g) and PPTS (339 mg). Purification by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) gave 1370 mg (90%) of the desired product.
1H NMR (300 MHz, CDCl3): xcex47.53 (dd, J=7.9, 0.7 Hz, 1H), 7.31-7.13 (m, 6H), 6.99(d, J=7.6 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.80-2.76 (m, 1H), 2.75 (t, J=7.5 Hz, 2H), 2.24-2.14 (m, 1H), 2.00-1.53 (m, 6H), 1.38 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4173.5, 167.1, 149.3, 142.1, 141.5, 128.6, 128.5, 126.0, 124.3, 123.9, 122.0, 117.7, 61.0, 35.6, 31.0, 28.7, 26.5, 23.0, 21.8, 16.3, 14.5.
LiAlH4 (152 mg) was added to a solution of 12a (1.036 g) in THF (20 mL). After stirring for 0.5 h, the reaction was quenched using the Fiesher method. The insolubles were removed by filtration and washed with THF. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 33% EtOAc/hexanes) to give 860 mg (99%) of the desired product.
1H NMR (300 MHz, CDCl3): xcex47.52 (dd, J=7.9, 1.0 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.95 (d, J=7.3 Hz, 1H), 3.68-3.63 (m, 2H), 3.06 (q, J=7.5 Hz, 2H), 2.18-2.12 (m, 1H), 1.77-1.66 (m, 1H), 1.51 (t, J=7.5 Hz, 3H), 1.67-1.60 (m, 1H), 1.35-1.21 (m, 1H), 1.09-1.06 (m, 1H); MS(ESI) 218 (M+H)+.
The title compound was prepared by the general procedure described in 13a using 12b (1.86 g), LAH (0.26 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 1.38 g (86%) of desired product.
1H NMR (300 MHz, CDCl3) xcex47.44 (d, J=7.9 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H). 6.88 (d, J=7.6 Hz, 1H), 3.76-3.62 (m, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.34 (br, s, 1H), 2.13-2.07 (m, 1H), 1.97-1.82 (m, 2H), 1.74-1.63 (m, 1H), 1.24-1.1.17 (m, 1H), 1.04 (t, J=7.4 Hz, 3H), 1.09-0.99 (m, 1H); 13C NMR (75 MHz, CDCl3) xcex4166.8, 149.3, 140.9, 125.9, 124.0, 121.1, 116.5, 66.1, 30.4, 24.0, 20.2, 16.3, 13.7, 12.5; MS (ESI): 232 (M+H)+.
The title compound was prepared by the general procedure described in 13a using 12c (1.87 g), LAH (0.26 g). Purification by flash chromatography over silica gel, elution with 30% EtOAc/hexanes, gave 1.57 g (100%) of desired product.
1H NMR (300 MHz, CDCl3) xcex47.47 (d, J=7.9 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H). 6.90 (d, J=7.7 Hz, 1H), 3.77-3.63 (m, 2H), 3.31-3.17 (m, 1H), 2.17-2.08 (m, 2H), 1.77-1.65 (m, 1H), 1.45 (d, J=7.0 Hz, 6H), 1.25-1.19 (m, 1H), 1.07-1.00 (m, 1H); 13C NMR (75 MHz, CDCl3) xcex4171.0, 149.2, 140.9, 125.9, 124.0, 121.2, 116.7, 66.2, 28.8, 24.0, 20.3, 16.3, 12.5; MS (ESI): 232 (M+H)+.
The title compound was prepared by the general procedure described above using 12d (1.3 g) and LiAlH4 (144 mg). Purification by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) gave 1080 mg (96%) of the desired product.
1H NMR (300 MHz, CDCl3): xcex47.49 (dd, J=7.9, 1.0 Hz, 1H), 7.31-7.16 (m, 6H), 6.92 (d, J=7.5 Hz, 1H), 3.76-3.62 (m, 2H), 2.98 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.14-1.68 (m, 6H), 1.26-1.00 (m, 2H); 13C NMR (75 MHz,CDCl3) xcex4167.0, 149.5, 142.1, 141.2, 128.6, 128.5, 126.1, 126.0, 124.3, 121.4, 116.8, 66.5, 35.6, 31.0, 28.7, 26.6, 24.3, 16.5, 12.8.
To a solution of oxalyl chloride (6.4 mol) in CH2Cl2 (8 mL) at xe2x88x9278xc2x0 C. under N2 was added DMSO (0.57) and stirred for 1 h. A solution of 13a (840 mg) in CH2Cl2 (12 mL) was added dropwise. After stirring for 1 h, the reaction was quenched with Et3N (2.2 mL) and allowed to warm to room temperature, and stirred for 1 h. The reaction was quenched with water. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 30% EtOAc/hexanes) to give 832 mg (99%) of the desired product.
IR (film, cmxe2x88x921) 1704; 1H NMR (300 MHz, CDCl3): xcex49.43 (d, J=4.5 Hz, 1H), 7.56 dd, J=8, 1.0 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.00 (d, J=7.4 Hz, 1H), 3.01 (q, J=7.5 Hz, 2H), 2.90-2.84 (m, 1H), 2.48-2.41 (m, 1H), 1.88-1.77 (m, 1H), 1.49 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,CDCl3) xcex4199.8, 168.3, 149.3, 141.5, 124.4, 122.7, 122.0, 118.1, 32.3, 22.3, 22.1, 15.7, 11.1; MS(ESI) 216 (M+H)+.
The title compound was prepared by the general procedure described in 14a using 13b (1.32 g), oxalyl chloride (4.3 ml), DMSO (0.89 g), Et3N (2.31 g) to give 1.31 g (100%) of crude product.
1H NMR (300 MHz, CDCl3) xcex49.41 (d, J=4.4 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H). 6.98 (d, J=7.6 Hz, 1H), 2.93-2.84 (m, 3H), 2.48-2.40 (m, 1H), 1.98-1.86 (m, 2H), 1.80 (t, J=7.4 Hz, 2H), 1.06 (t, J=7.4 Hz, 3H).
The title compound was prepared by the general procedure described in 14a using 13c (1.54 g), oxalyl chloride (5.0 ml), DMSO (1.04 g), Et3N (2.70 g) to give 1.51 g (99%) of crude product.
1H NMR (300 MHz, CDCl3) xcex49.41 (d, J=4.5 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H). 6.98 (d, J=7.6 Hz, 1H), 3.31-3.17 (m, 1H), 2.91-2.84 (m, 1H), 2.48-2.40 (m, 1H), 1.80 (dd, J=8.0, 5.6 Hz, 2H), 1.45 (d, J=7.0 Hz, 3H).
The title compound was prepared by the general procedure described in 14a using 13d (1.02 g), oxalyl chloride (2.4 ml), DMSO (0.50 g), Et3N (1.28 g) to give 1.01 g (100%) of crude product.
1H NMR (300 MHz, CDCl3) xcex49.42 (d, J=4.4 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.31-7.16 (m, 6H). 6.99 (d, J=7.7 Hz, 1H), 2.97 (t, J=7.4 Hz, 2H), 2.92-2.84 (m, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.48-2.40 (m, 1H), 2.00-1.89 (m, 2H), 1.84-1.73 (m, 2H), 1.42 (t, J=7.4 Hz, 2H).
To a mixture of 14a (800) and NH2OH.HCl (777 mg) in THF (22 mL) was added 1 N NaOH (11.1 mL). The resulting mixture was refluxed for 1 h. After THF was removed, the residue was extracted with EtAcO, washed with brine, dried over MgSO4, and concentrated to give 851 mg (100%) of the desired product that was used in the next step without purification. (IR (film, cmxe2x88x921) 3236; MS(ESI) 231 (M+H)+.) NaBH4 (1.368 g) was added to a solution of the above product (851 mg) and cobalt (II) chloride hexahydrate, CoCl2.6H2O, (3.427 g) at 0xc2x0 C. After stirring for 1 h, the reaction was quenched with 6 N HCl and MeOH was removed to give a residue. The residue was based with NH4OH solution, extracted with EtOAc. The organic layer was washed with brine and concentrated to give 600 mg (77%) of the desired product that was used in the next step without purification.
The title compound was prepared by the general procedure described in 15a using 14b (1.31 g), hydroxylamine hydrochloride (1.19 g), NaOH(1N, 17 ml) to give an oxime intermediate which was treated with sodium borohydride (2.04 g) and cobalt (II) chloride hexahydrate (5.14 g) to afford 1.18 g (89%) of crude amine which was taken to the next step without further purification. MS (ESI): 231 (M+H)+.
The title compound was prepared by the general procedure described in 15a using 14c (1.46 g), hydroxylamine hydrochloride (1.32 g), NaOH (1N, 20 ml) to give an oxime intermediate which was treated with sodium borohydride (2.06 g) and cobalt (II) chloride hexahydrate (5.18 g) to afford 1.13 g (77%) of crude amine which was taken to the next step without further purification. MS (ESI): 231 (M+H)+.
The title compound was prepared by the general procedure described in 15a using 14d (1.01 g), hydroxylamine hydrochloride (0.66 g), NaOH(1N, 10 ml) to give an oxime intermediate which was treated with sodium borohydride (1.01 g) and cobalt (II) chloride hexahydrate (2.53 g) to afford 0.50 g (49%) of crude amine which was taken to the next step without further purification. MS (ESI): 321 (M+H)+.